Abnormal Ontogeny and Cortical Function in a Mouse Model Early stress experience is regarded as powerfully contributing factor in the etiology of mental health disorders such as schizophrenia and mood disorders. Early stress experience leads to permanent alterations in the adreno-cortical-hypothalamic [HPA] response in later life. In rodent models, long-term, early postnatal maternal separation [MS] (3-24 hours) leads to profound HPA hyper-responsiveness to stress in later life, along with increased anxiety and impaired cognition. However, early, short term "handling" of pups (10-15 minutes) results in long-term stress hypo-responsiveness, decreased anxiety and improved cognition, apparently as result of increased maternal grooming of the handled pups upon their return. Over the current funding period, we have developed a neonatal MS separation paradigm in mouse, based on a split-litter design. Stressed male mice [STR] from these liters develop cognitive impairments, increased anxiety and aggression by adulthood, and, altered cortical width, that is modifiable by experience. Surprisingly, non-stressed litter-mate males [LMC] also develop cortical changes and cognitive and emotional impairments, albeit at somewhat lower levels, compared to age matched control [AMC] mice from litters without any stress exposure. Preliminary data suggest decreased maternal grooming of LMC compared to STR pups. This proposal aims to test the hypotheses that 1) maternal grooming of the STR and LMC pups induces graded effects on early HPA axes responsiveness that subsequently, differentially alter the monoaminergic innervation to cortex and hippocampus. Furthermore, based on effects of neonatal serotonin [5-HT] and dopamine [DA] depletions on cortical morphogenesis and plasticity, we hypothesize that 2) cortical morphological differences in both STR and LMC, compared to AMC mice, are the result of impaired cortical morphogenesis and plasticity resulting from altered 5-HT and/or DA innervation; such morphological changes, in turn, may precipitate altered behavior. The long-term goal of this competitive renewal application is to understand, on the level of cellular neurobiology, how developmental interactions between environmental triggers and genetic vulnerabilities can induce altered cognitive function akin to those seen in a variety of mental health disorders.